The erythropoietin receptor expressed in skeletal muscle is essential for mitochondrial biogenesis and physiological exercise

Abstract

Erythropoietin (EPO) is a haematopoietic hormone that regulates erythropoiesis, but the EPO-receptor (EpoR) is also expressed in non-haematopoietic tissues. Stimulation of the EpoR in cardiac and skeletal muscle provides protection from various forms of pathological stress, but its relevance for normal muscle physiology remains unclear. We aimed to determine the contribution of the tissue-specific EpoR to exercise-induced remodelling of cardiac and skeletal muscle. Baseline phenotyping was performed on left ventricle and m. gastrocnemius of mice that only express the EpoR in haematopoietic tissues (EpoR-tKO). Subsequently, mice were caged in the presence or absence of a running wheel for 4 weeks and exercise performance, cardiac function and histological and molecular markers for physiological adaptation were assessed. While gross morphology of both muscles was normal in EpoR-tKO mice, mitochondrial content in skeletal muscle was decreased by 50%, associated with similar reductions in mitochondrial biogenesis, while mitophagy was unaltered. When subjected to exercise, EpoR-tKO mice ran slower and covered less distance than wild-type (WT) mice (5.5 ± 0.6 vs. 8.0 ± 0.4 km/day, p < 0.01). The impaired exercise performance was paralleled by reductions in myocyte growth and angiogenesis in both muscle types. Our findings indicate that the endogenous EPO-EpoR system controls mitochondrial biogenesis in skeletal muscle. The reductions in mitochondrial content were associated with reduced exercise capacity in response to voluntary exercise, supporting a critical role for the extra-haematopoietic EpoR in exercise performance.

Pan-Cancer Analysis Based on EPOR Expression With Potential Value in Prognosis and Tumor Immunity in 33 Tumors

“…EPOR is present not only in hematopoietic cells but also in non-hematopoietic cells such as neurons ( 10 ), endothelial cells ( 11 ), and skeletal muscle cells ( 33 ) and in various tumors such as breast cancer ( 34 ) and head and neck cancer ( 35 ). Regarding EPOR expression in cancers, on the one hand, it is believed that EPOR expression is upregulated, such as in prostate cancer ( 21 ) and glioma ( 22 ); on the other hand, no significant EPOR expression was detected in tumor cell lines and solid tumor specimens, and Swift et al.…”

“…Therefore, in the study, we aimed to explore the feasibility of EPOR as a prognostic marker and its role in tumor immunity, tumor occurrence, and progression through bioinformatics techniques. EPOR is present not only in hematopoietic cells but also in non-hematopoietic cells such as neurons (10), endothelial cells (11), and skeletal muscle cells (33) and in various tumors such as breast cancer (34) and head and neck cancer (35). Regarding EPOR expression in cancers, on the one hand, it is believed that EPOR expression is upregulated, such as in prostate cancer (21) and glioma (22); on the other hand, no significant EPOR expression was detected in tumor cell lines and solid tumor specimens, and Swift et al (36) suggested that low levels of EPOR expression are common in tumor cell lines, Elliott et al (37) questioned the assumption that most tumors express high levels of functional EPOR proteins, and Patterson et al (38) did not detect the utilization of the functional EPOR pathway in primary tumor cells isolated from tumor tissues such as human breast cancer.…”

Physical Training Increases Erythroferrone Levels in Men

“…Animal studies with mouse models have shown a 4–7 fold increase in EPO mRNA expression in skeletal muscle following exercise, and the increase was higher in glycolytic muscles and for trained mice [ 26 ]. The most recent data indicate that the endogenous EPO, through the EPO receptor in myocytes, controls mitochondrial biogenesis in skeletal muscle [ 27 ]. Nijholt et al showed that a lack of EPO receptors in non-haematopoietic tissues lead to low mitochondrial content in skeletal muscles, as well as reduced myocyte growth and exercise capacity in response to voluntary exercise in mice [ 27 ].…”

“…The most recent data indicate that the endogenous EPO, through the EPO receptor in myocytes, controls mitochondrial biogenesis in skeletal muscle [ 27 ]. Nijholt et al showed that a lack of EPO receptors in non-haematopoietic tissues lead to low mitochondrial content in skeletal muscles, as well as reduced myocyte growth and exercise capacity in response to voluntary exercise in mice [ 27 ]. Thus, it may be suggested that the source of erythropoietin released into circulation as a result of physical exertion may not only be from the kidneys but—at least in the early stages of exercise—from the working skeletal muscles as well [ 27 ].…”

Exercise: a molecular tool to boost muscle growth and mitochondrial performance in heart failure?

“…In skeletal muscle, improvements in mitochondrial quality control could enhance the adaptive response to stress and block or reverse the unfavourable muscle fibre switching. Recently, our department uncovered an important role of the erythropoietin receptor in skeletal muscle, a novel target which is critical for mitochondrial biogenesis in skeletal muscle and the response to physiological exercise 155 . Potentially, stimulating skeletal muscle erythropoietin signalling could benefit for patients with mitochondrial myopathies, skeletal muscle fatigue, or atrophy.…”